This article will be published in the next edition of the Alpha-1 Association's Alpha-1 News. Enjoy this advanced preview. Copyrights apply.
The road to a cure for Alpha-1 just became a little more enlightened. Dr. Jeffrey Teckman, Associate Professor/Director of the Division of Gastroenterology & Hepatology at Saint Louis University, recently published a groundbreaking research study in the journal Hepatology. The title of that study, Alpha-1 Antitrypsin Mutant Z Protein Content in Individual Hepatocytes Correlates with Cell Death in a Mouse Model, might seem a bit daunting, but rest assured Dr. Teckman’s clarity about his research shines through.
Dr. Teckman’s research team has a goal to figure out how the liver gets hurt in Alpha-1 Antitrypsin Deficiency. Essentially, experts have known that the build up of the Z protein in the liver is what damages the liver. This knowledge was built off of experiments that were conducted in vitro, also known as cells in a dish.
Dr. Teckman clarified, “That is useful, but it is a long way from a cell in a dish to a liver because in a dish, all the cells are the same.” Dr. Teckman wanted to take a big step forward and move that knowledge into an animal research model. Applying theories using animal research models is a critical step of research aimed at finding a cure for Alpha-1. Dr. Teckman further clarified, “In the liver, there are many different types of cells, and the cells are arranged in a very complex arrangement. Those may be important factors that are difficult to model just in a dish.”
Dr. Teckman’s team worked for the last four years to answer questions about how the Z protein causes damage in the liver. He added, “Part of the way that cells die is a process called apoptosis. That is a common way for cells to die, but the problem was that we couldn’t figure out why the whole liver just didn’t die. Because there is a lot of Alpha-1 in the liver, we focused our study on answering questions such as: Are liver cells dying because of apoptosis? And if they are, why doesn’t the whole liver just die from apoptosis? How could we understand that?”
Dr. Teckman shared, “And so it turns out that within the liver, the build up of the abnormal protein is very heterogeneous. So some cells build up very large amounts, and some cells don’t build up any. The liver cells with the most Alpha-1 tend to die from apoptosis; however, certain cells seem to detect the buildup of Alpha-1. Those cells “decide” to try to stay alive. That process works well. There are only a small handful of cells at any one time that are having trouble, and it is this very slow turnover of cells in the liver which make this disease slowly progressive in most people.”
So in finding answers to those questions, Dr. Teckman’s team formed more questions that need answers. “It is 5-10% of Alphas, who seem to have trouble, and then the other 90% do fine. We still need to figure out the differences between the group who does fine and the group who doesn’t. With this study, we are beginning to understand about the 90% who do well. This study isn’t the final answer though. We think this an important step on the way to finding the final answer, and especially for developing a kind of a flow chart for how the liver gets hurt. That allows researchers to investigate every arrow in the chart, and figure out a medicine that could block certain “arrows” in the chart.”
Dr. Teckman envisions this for the future, “Now we are trying to understand the liver cells that have the large amount of Z protein build-up. We are trying to determine what that build-up might mean in terms of developing liver cancer. We are also trying to test drugs that would block the build up of abnormal protein so we can hopefully take some of these drugs we are testing in animals and then try them in humans in clinical trials.”
The research sounds very promising. Dr. Teckman added, “Well, we hope so. It takes time and money to fund research. That is why we need to increase funding into Alpha-1."
Dr. Teckman's study was funded by the National Institutes of Health (NIH) as well as the Alpha-1 Foundation.